ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.536_553del (p.Asp179_Leu184del) (rs794727835)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000675172 SCV000800795 likely pathogenic Homocystinuria due to CBS deficiency 2017-11-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413538 SCV000232001 uncertain significance not provided 2014-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000413538 SCV000491080 likely pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing The c.536_553del18 variant in the CBS gene has been reported in patients with homocystinuria due to CBS deficiency (Kraus et al. 1999; Ruhoy et al. 2014). This variant results in an in-frame deletion of 6 amino acids starting at codon Aspartic acid 179, denoted p.D179_L184. This deletion occurs in a conserved region of the CBS protein and other in-frame deletions in CBS have been reported in the Human Gene Mutation Database (HGMD) in association with homocystinuria due to CBS deficiency (Stenson et al., 2014). The c.536_553del18 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.536_553del18 to be likely pathogenic.
Invitae RCV000675172 SCV000834206 pathogenic Homocystinuria due to CBS deficiency 2018-12-05 criteria provided, single submitter clinical testing This variant, c.536_553del, results in the deletion of 6 amino acid(s) of the CBS protein (p.Asp179_Leu184del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CBS variant in individuals affected with CBS-deficiency (PMID: 12124992, 24138954, Invitae). ClinVar contains an entry for this variant (Variation ID: 198388). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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